Vitamins K are structurally related compounds, that share the 2-methyl-1,4-naphthoquinone ring but differ in the saturation and the number of attached side chains. The group of vitamins K includes two natural vitamers: vitamin K1 (also known as phylloquinone or phytomenadione), containing phytin residue at C-3 position, vitamins K2 (called menaquinones or pharnoquinones), characterized by the menadione structure with polyprenyl side chain at C-3 position, as well as a number of easily fat and water soluble synthetic derivatives such as vitamin K3 (menadione). Molecular structures of different vitamins K are represented by the formulae depicted below:

Menachinones (MK-n) have the different isoprene units number in the side chain (n=1-13). Different biological activity and bioavailability of menaquinones (MK-n) result from the chain length and the number of unsaturated bonds present in that side chain [Chemistry of Natural Compound 2007, 43(3), 277-281].
Vitamin K, as a cofactor of γ-carboxylase, is involved in posttranslational γ-carboxylation of certain glutamate residues in precursor proteins PIVKA. Vitamin K is necessary for the biosynthesis and maintenance at the appropriate level of coagulation factors II, VII, IX and X, osteocalcin, osteopontin, osteonectin and also calcium binding protein in kidneys, placenta and lungs. Vitamin K is involved in the coagulation cascade in animals and its presence is essential for the proper synthesis of blood clotting proteins, participating in the coagulation homeostasis. It also contributes to strong bones formation, preventing from osteoporosis development. Vitamin K also exerts anti-bacterial, anti-fungal, anti-inflammatory and pain relief activities. Recently, it has been proved that vitamin K2 may substantially affect the condition of arterial walls and blood circulation.
Vitamin K is not produced by human tissue. It is found in green plants, such as green leafy vegetables (spinach, broccoli, cabbage, lettuce, green tea). Vitamin K2 is synthesized by bacteria, therefore it is present in abundance in fermented food products, like for example: cheese, yogurt, sauerkraut. Meat also contains vitamin K, and MK-7 is found in large quantities (about 10 μg/g) in fermented soybean seeds. Since vitamin K is produced by intestinal bacteria, the human body is usually provided with enough quantities of this vitamin. However, it is observed that a long term treatment with sulfonamides and antibiotics may cause deficiency or extinction of the beneficial intestinal microflora (avitaminosis or hypovitaminosis).
Daily vitamin K requirements is usually about 2 mg. Individual diet and bioavailability are the critical parameters to maintain proper level of vitamin K in a human body. Vitamin K1 is poorly absorbed in humans (5-10%), and for the same reason synthetic MK-4 type of vitamin K2 is recommended to be administered at large quantities and frequent doses. The numerous trials have evidenced that the highest biological activity of all vitamin K homologues has MK-7 type of vitamin K2:

MK-7 type of vitamin K2 is characterized by better bioavailability and efficacy than the other vitamins K. It is also characterized by the high absorption in small intestine and sustained presence in a blood serum (up to 3 days). Even small daily doses of vitamin MK-7 are sufficient to provide all cells and tissues with vitamin K dependent enzymes and proteins at the proper level. On account of participation in calcium metabolism, vitamin MK-7 is indirectly involved in strong bones formation. Unlike vitamin K1, it also influences arterial vessel wall condition.
Vitamin MK-7 structure consists of naphthalenedione ring (menadione) with the attached alkyl chain comprising seven isoprene units (heptaprenyl), thus it contains seven double bounds of trans configuration. Considering its molecular structure, synthetic vitamin MK-7 could be synthesized from menadione or its protected derivative, menadiol, following one of the strategies mentioned below:
1. attachment of heptaprenyl chain directly to menadiol molecule, according to so called “0+7” strategy;
2. attachment of chain shorter fragments to monoprenyl derivative of menadiol, according to “1+n+m” strategy;
3. attachment of hexaprenyl chain to monoprenyl derivative of menadiol, according to “1+6” strategy.
U.S. Pat. No. 4,199,531 discloses the process for elongation of the side chain of menadiol derivative having at position C-3 from 1 to n terminal activated isoprenyl units, accomplished by its stereo- and regio-selective alkylation with activated side chain precursor consisting of m isoprenyl units. The carbanion generated under basic conditions on the carbon atom adjacent to arylthio, arylsulfinyl or arylsulfonyl terminal group of one substrate is subsequently alkylated with alkyl halide as the second substrate. Then, in case of the reaction of monoprenylmenadiol arylsulfonyl derivative with polyprenyl halide, the product is subjected to reductive desulfonylation, deprotection of the hydroxyl groups if there is a need thereof, and/or oxidation to afford menaquinone derivative. According to the specification, alkylation is performed under the basic conditions, in the presence of bases such as butyllithium or phenyllithium, under dry conditions; in a solvent such as tetrahydrofurane, ether or 1,2-dimethoxyethane; at −78° C. to 20° C. temperature range. Although the general chemical formula comprises the chemical structure of vitamin MK-7, no specific preparative example for this vitamin synthesis is given in the specification.
The above mentioned process for alkylation of phenylsulfonyl derivative of monoprenylmenadiol using triprenyl halide yielding vitamin MK-4 (according to “1+3 strategy”) has been described in J. Org. Chem. 2003, 68, 7925. There has also been disclosed the synthesis of phenylsulfonyl derivative of monoprenyl menadiol dimethoxy-ether (MK-1) from menadiol.
In the International Patent Application WO 2011/117324, multi-step process for preparation of polyisoprenyl alcohols and halides having different length chains in Biellmann type reaction has been disclosed. The coupling reaction of arylsulfonyl or arylthiol polyisoprenyl derivative having p isoprenyl units (p=0-4) with the properly protected (for example with the acetyl groups) primary polyisoprenyl halide having q isoprenyl units (q=0-4) is carried out in the presence of a non-nucleophilic base. Subsequent removal of SO2Ar or SAr group under reductive conditions, followed by deprotection of hydroxyl group, furnishes the desired product. In Example 6, synthesis of pentaprenyl alcohol from diprenyl-alcohol bromide, having protected acetyl and phenylsulfonyltriprenyl groups, is described. After each step of the process: alkylation, desulfonylation and removal of hydroxyl protecting groups, purification of the product by silica gel flash chromatography is necessary. Polyprenyl halides obtained according to this procedure have been used in the vitamins K2 synthesis, in particular vitamin MK-7 synthesis, under Grignard/Kumada or Suzuki conditions, following “0+7” or “2+5” strategy.
Publication WO 2010/03500 discloses the synthesis of vitamin K2 that is based on the polyprenyl ring attachment to the protected activated menadiol derivative, under Grignard/Kumada or Suzuki conditions, according to “0+7 strategy”.
In the two aforementioned International Patent Applications, the activated menadione derivative with carbonyl functions protected with alkyl or benzyl groups, as the potential synthetic substrate has been claimed. However, in the preparative examples only methoxy-derivatives of menadiol have been used.
The aim of the present invention was to develop the process for preparation of synthetic all-trans vitamin MK-7, in which easily available substrates could be used.
Moreover, the aim of the invention was to develop the process enabling the preparation of vitamin MK-7 characterized by high purity, which would meet the quality requirements approved for both the dietary supplements as well as active pharmaceutical ingredients.
The further aim of the present invention was to provide vitamin MK-7 of demanded purity in a high yield, in a process optimized to eliminate or reduce the troublesome and time-consuming multiple chromatographic purifications of all intermediates.
These goals have been achieved due to coupling of a hexaprenyl chain precursor of all-trans configuration with a menadiol derivative bearing the phenylsulfonyl monoprenyl terminal group and protected in the form of alkoxy-ethers, especially in the form of ethoxy-ether. Unexpectedly, it has appeared that this phenylsulfonyl monoprenyl menadiol ethoxy-derivative could be obtained in a crystalline form, that significantly improves the process of its purification. Low level of impurities accompanying this new derivative, enables preparation of all-trans configuration vitamin MK-7 of the high purity, with the limited necessity of purifications of intermediates by means of preparative chromatography.